Factors associated with persistent opioid use 6-12 months after primary total knee arthroplasty.

Persistent pain following knee arthroplasty occurs in up to 20% of patients and may require ongoing analgesia, including extended opioid administration. A comprehensive secondary analysis was performed from results of a study that considered persistent postoperative pain in 242 patients who underwent unilateral knee arthroplasty using a standardised enhanced recovery programme. Opioid prescribing for 12 months before and 12 months after surgery was evaluated and converted to oral morphine equivalents. Demographic, functional, psychological and pain questionnaires were completed along with quantitative sensory testing and genetic analysis. Forty-nine percent of patients had at least one opioid prescription in the 12 months before surgery. Opioid prescriptions were filled in 93% of patients from discharge to 3 months and in 27% of patients ≥6 months after surgery. Persistent opioid use ≥6 months after surgery was strongly associated with pre-operative opioid use (RR 3.2, p < 0.001 (95%CI 1.9-5.4)). The median (IQR [range]) oral morphine equivalent daily dose was 3.6 (0.9-10.5 [0-100.0]) mg pre-operatively, 35.0 (22.5-52.5 [4.6-180.0]) mg in hospital, 12.8 (5.1-24.8 [0-57.9]) mg from discharge to 3 months and 5.9 (4.5-12.0 [0-44.5]) mg at ≥6 months following surgery. Predictors of increased daily oral morphine equivalent ≥6 months after surgery included increased average daily oral morphine equivalent dose compared with previous values (lag), increased body mass index and three or more comorbid pain sites. Persistent opioid use was not associated with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain (RR 1.003, p = 0.655, 95%CI 0.65-1.002) or WOMAC function (RR 1.001, p = 0.99, 95%CI 0.99-1.03) outcomes 6 months after surgery. There was no association between persistent opioid use and pre-operative quantitative sensory testing results or psychological distress. Pre-operatively, patients with a higher body mass index, more comorbid pain sites and those who had filled an opioid prescription in the last 12 months, were at increased risk of persistent opioid use and a higher oral morphine equivalent daily dose ≥ 6 months after surgery. Strategies need to be developed to limit dose and duration of persistent opioid use in patients following knee arthroplasty surgery.

Persistent postoperative pain after total knee arthroplasty: a prospective cohort study of potential risk factors.

BACKGROUND: Persistent postoperative pain (PPP) is common after total knee arthroplasty (TKA). The primary aim of this prospective cohort study was to identify important predictors of moderate to severe PPP 6 and 12 months after TKA. METHODS: Consenting patients (n=300) undergoing primary unilateral TKA attended a preoperative session to collect clinical information (age, gender, BMI, preoperative knee pain, comorbid pain, likely neuropathic pain) and psychological variables (depression, anxiety, catastrophising, expected pain). Quantitative sensory testing (pressure pain thresholds, temporal summation, conditioned pain modulation) was performed, and blood samples were obtained for subsequent genotyping of OPRM1 and COMT. Acute postoperative pain was measured at rest and during movement. Surgical factors (surgery time, patella resurfacing, anaesthetic type) were collected after operation. Follow-up questionnaires were sent 6 and 12 months after surgery. Multivariate logistic regression was used to identify predictors of PPP. RESULTS: The prevalence of moderate to severe PPP was 21% (n=60) and 16% (n=45) 6 and 12 months after surgery, with 55% (n=33) and 60% (n=31) of PPP likely neuropathic in nature. At 6 months, a combination of preoperative pain intensity, expected pain, trait anxiety, and temporal summation (Akaike information criterion, 309.9; area under receiver operating characteristic (ROC) curve, 0.70) was able to correctly classify 66% of patients into moderate to severe PPP and no to mild PPP groups. At 12 months, preoperative pain intensity, expected pain, and trait anxiety (Akaike information criterion, 286.8; area under ROC curve, 0.66) correctly classified 66% of patients. CONCLUSIONS: Findings from this study highlight several factors that may be targeted in future intervention studies to reduce the development of PPP. TRIAL REGISTRY NUMBER: ACTRN12612001089820.

Effects of articaine on [3H]noradrenaline release from cortical and spinal cord slices prepared from normal and streptozotocin-induced diabetic rats and compared to lidocaine.

Since a significant proportion of diabetic patients have clinical or subclinical neuropathy, there may be concerns about the use of local anaesthetics. The present study was designed to determine and compare the effects of articaine, a widely used anaesthetic in dental practice, and lidocaine on the resting and axonal stimulation-evoked release of [3H]noradrenaline ([3H]NA) in prefrontal cortex slices and the release of [3H]NA in spinal cord slices prepared from non-diabetic and streptozocin (STZ)-induced diabetic (glucose level=22.03±2.31mmol/l) rats. The peak of allodynia was achieved 9 weeks after STZ-treatment. Articaine and lidocaine inhibited the stimulation-evoked release in a concentration-dependent manner and increased the resting release by two to six times. These effects indicate an inhibitory action of these anaesthetics on Na+- and K+-channels. There was no difference in clinically important nerve conduction between non-diabetic and diabetic rats, as measured by the release of transmitter in response to axonal stimulation. The uptake and resting release of NA was significantly higher in the brain slices prepared from diabetic rats, but there were no differences in the spinal cord. For the adverse effects, the effects of articaine on K+ channels (resting release) are more pronounced compared to lidocaine. In this respect, articaine has a thiophene ring with high lipid solubility, which may present potential risks for some patients.

Patterns of metal distribution in hypersaline microbialites during early diagenesis: Implications for the fossil record.

The use of metals as biosignatures in the fossil stromatolite record requires understanding of the processes controlling the initial metal(loid) incorporation and diagenetic preservation in living microbialites. Here, we report the distribution of metals and the organic fraction within the lithifying microbialite of the hypersaline Big Pond Lake (Bahamas). Using synchrotron-based X-ray microfluorescence, confocal, and biphoton microscopies at different scales (cm-µm) in combination with traditional geochemical analyses, we show that the initial cation sorption at the surface of an active microbialite is governed by passive binding to the organic matrix, resulting in a homogeneous metal distribution. During early diagenesis, the metabolic activity in deeper microbialite layers slows down and the distribution of the metals becomes progressively heterogeneous, resulting from remobilization and concentration as metal(loid)-enriched sulfides, which are aligned with the lamination of the microbialite. In addition, we were able to identify globules containing significant Mn, Cu, Zn, and As enrichments potentially produced through microbial activity. The similarity of the metal(loid) distributions observed in the Big Pond microbialite to those observed in the Archean stromatolites of Tumbiana provides the foundation for a conceptual model of the evolution of the metal distribution through initial growth, early diagenesis, and fossilization of a microbialite, with a potential application to the fossil record.

Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression.

OBJECTIVE: This pilot study assessed the feasibility, efficacy and safety of an individual dose-titration approach, and of the intravenous (IV), intramuscular (IM) and subcutaneous (SC) routes for treating depression with ketamine. METHOD: Fifteen treatment-refractory depressed participants received ketamine or midazolam (control treatment) in a multiple crossover, double-blind study. Ketamine was administered by IV (n = 4), IM (n = 5) or SC (n = 6) injection. Dose titration commenced at 0.1 mg/kg, increasing by 0.1 mg/kg up to 0.5 mg/kg, given in separate treatment sessions separated by ≥1 week, with one placebo control treatment randomly inserted. Mood, psychotomimetic and hemodynamic effects were assessed and plasma ketamine concentrations assayed. RESULTS: Twelve participants achieved response and remission criteria, achieved at doses as low as 0.1 mg/kg. All three routes of administration resulted in comparable antidepressant effects. Fewest adverse effects were noted with the SC route. Antidepressant response, adverse effects and ketamine concentrations were dose-related. CONCLUSION: Antidepressant response occurred at a range of doses and at <0.5 mg/kg. The dose-titration approach is a practical method for optimizing the efficacy - side-effects trade-off on an individual patient basis. This pilot study provides preliminary evidence for SC injection as a practical, feasible and efficacious treatment approach.

Pharmacogenetics of opioid response.

For opioids requiring CYP2D6 O-demethylation to active metabolites, poor metabolizers have reduced metabolite formation and minimal pain reduction. Clinically, this has only reliably been shown for tramadol. Ultra-rapid metabolizers have an increased risk of toxicity especially for codeine. ABCB1 genetics show no consistent findings. In Asian populations, the high OPRM1 118A>G frequency associates with higher opioid dosage requirements. Clinical translation of opioid genetics is premature because many important pain and addiction phenotype factors contribute.

Multicenter evaluation of the Sepsityper™ extraction kit and MALDI-TOF MS for direct identification of positive blood culture isolates using the BD BACTEC™ FX and VersaTREK(®) diagnostic blood culture systems.

AIMS: (i) Evaluation of delayed time to blood culture extraction by the Sepsityper kit and impact of shipping pellets off-site for MALDI-TOF MS analysis. (ii) Comparison of Sepsityper and laboratory-developed extraction methods from a literature review. METHODS AND RESULTS: Using two blood culture systems (BD BACTEC and VersaTREK), we extracted 411 positive blood cultures using the Sepsityper kit to mimic a potential protocol for institutions without a MALDI-TOF MS. Extracted pellets were shipped and analysed on the Bruker UltraflexIII. Successful extraction of 358 (87·1%) samples was determined by the presence of detectable proteins. MALDI-TOF MS correctly identified 332 (80·8%) samples. CONCLUSIONS: Delayed time to extraction did not affect Sepsityper extraction or MALDI-TOF MS accuracy. The extracted pellets remain stable and provide accurate results by MALDI-TOF MS when shipped at room temperature to off-site reference laboratories. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study to show that institutions without a MALDI-TOF MS can take advantage of this innovative technology by shipping a volume of blood to an off-site laboratory for extraction and MALDI-TOF MS analysis. We also performed a literature review to compare various extraction methods.

Opioid activation of toll-like receptor 4 contributes to drug reinforcement.

Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here, we present evidence for an additional novel contributor to opioid reward: the innate immune pattern-recognition receptor, toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the nonopioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knock-outs of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4(-/-) mice had reduced oxycodone-induced p38 and JNK phosphorylation, while displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively, these data indicate that the actions of opioids at classical opioid receptors, together with their newly identified TLR4/MD2 actions, affect the mesolimbic dopamine system that amplifies opioid-induced elevations in extracellular dopamine levels, therefore possibly explaining altered opioid reward behaviors. Thus, the discovery of TLR4/MD2 recognition of opioids as foreign xenobiotic substances adds to the existing hypothesized neuronal reinforcement mechanisms, identifies a new drug target in TLR4/MD2 for the treatment of addictions, and provides further evidence supporting a role for central proinflammatory immune signaling in drug reward.

Formation of amino acids and nucleotide bases in a Titan atmosphere simulation experiment.

The discovery of large (>100 u) molecules in Titan's upper atmosphere has heightened astrobiological interest in this unique satellite. In particular, complex organic aerosols produced in atmospheres containing C, N, O, and H, like that of Titan, could be a source of prebiotic molecules. In this work, aerosols produced in a Titan atmosphere simulation experiment with enhanced CO (N(2)/CH(4)/CO gas mixtures of 96.2%/2.0%/1.8% and 93.2%/5.0%/1.8%) were found to contain 18 molecules with molecular formulae that correspond to biological amino acids and nucleotide bases. Very high-resolution mass spectrometry of isotopically labeled samples confirmed that C(4)H(5)N(3)O, C(4)H(4)N(2)O(2), C(5)H(6)N(2)O(2), C(5)H(5)N(5), and C(6)H(9)N(3)O(2) are produced by chemistry in the simulation chamber. Gas chromatography-mass spectrometry (GC-MS) analyses of the non-isotopic samples confirmed the presence of cytosine (C(4)H(5)N(3)O), uracil (C(5)H(4)N(2)O(2)), thymine (C(5)H(6)N(2)O(2)), guanine (C(5)H(5)N(5)O), glycine (C(2)H(5)NO(2)), and alanine (C(3)H(7)NO(2)). Adenine (C(5)H(5)N(5)) was detected by GC-MS in isotopically labeled samples. The remaining prebiotic molecules were detected in unlabeled samples only and may have been affected by contamination in the chamber. These results demonstrate that prebiotic molecules can be formed by the high-energy chemistry similar to that which occurs in planetary upper atmospheres and therefore identifies a new source of prebiotic material, potentially increasing the range of planets where life could begin.

Contrasting effects of diclofenac and ibuprofen on active imatinib uptake into leukaemic cells.

BACKGROUND: The human organic cation transporter-1 (OCT-1) is the primary active protein for imatinib uptake into target BCR-ABL-positive cells. Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used by chronic myeloid leukaemia (CML) patients on imatinib to manage musculoskeletal complaints. METHODS: Here we investigated the impact of NSAIDs on functional activity of the OCT-1 (OCT-1 activity; OA) in CML cells. RESULTS: Although ten of twelve NSAIDs tested had no significant impact on OA (P>0.05), we observed increased OA (27% increase in K562; 22% increase in KU812 cells, P<0.05) and reduced IC50(imatinib) when treated with diclofenac. Co-incubation with imatinib and diclofenac resulted in a significantly lower viable cell number compared with imatinib alone. In contrast, ibuprofen led to a significant decrease in OA, an increase in IC50(imatinib) and thus reduced the cytotoxicity of imatinib. In primary CML samples, diclofenac significantly increased OA, particularly in patients with low OA (<4 ng per 200 000 cells), and significantly decreased IC50(imatinib). Ibuprofen induced significant decreases in OA in CML samples and healthy donors. CONCLUSION: On the basis of the expected impact of these two drugs on OA, ibuprofen should be avoided in combination with imatinib. Further studies are warranted regarding the potential benefit of diclofenac to improve OA in a clinical setting.

Acute pain management in opioid-tolerant patients: a growing challenge.

In Australia and New Zealand, in parallel with other developed countries, the number of patients prescribed opioids on a long-term basis has grown rapidly over the last decade. The burden of chronic pain is more widely recognised and there has been an increase in the use of opioids for both cancer and non-cancer indications. While the prevalence of illicit opioid use has remained relatively stable, the diversion and abuse of prescription opioids has escalated, as has the number of individuals receiving methadone or buprenorphine pharmacotherapy for opioid addiction. As a result, the proportion of opioid-tolerant patients requiring acute pain management has increased, often presenting clinicians with greater challenges than those faced when treating the opioid-naïve. Treatment aims include effective relief of acute pain, prevention of drug withdrawal, assistance with any related social, psychiatric and behavioural issues, and ensuring continuity of long-term care. Pharmacological approaches incorporate the continuation of usual medications (or equivalent), short-term use of sometimes much higher than average doses of additional opioid, and prescription of non-opioid and adjuvant drugs, aiming to improve pain relief and attenuate opioid tolerance and/or opioid-induced hyperalgesia. Discharge planning should commence at an early stage and may involve the use of a 'Reverse Pain Ladder' aiming to limit duration of additional opioid use. Legislative requirements may restrict which drugs can be prescribed at the time of hospital discharge. At all stages, there should be appropriate and regular consultation and liaison with the patient, other treating teams and specialist services.

Preserved structural and functional characteristics of common carotid artery in properly treated normoglycemic women with gestational diabetes mellitus.

Women with gestational diabetes mellitus (GDM) are at high risk of subsequently developing type 2 diabetes mellitus which is an important cardiovascular risk factor. We have evaluated whether preclinical morphological and functional arterial changes are present in GDM. Diameter, intima-media thickness (IMT), intima-media cross-section area (IMCSA) and elasticity features (compliance, distensibility coefficient, circumferential strain, stiffness index (SI) α and ß, incremental elastic modulus) of the common carotid arteries (CCA) were studied in the 3rd trimester in 25 women with GDM, and 17 normal pregnant women matched for age and body mass index using an ultrasonographic vessel wall-movement tracking system and applanation tonometry. Mean IMT, IMCSA and SI α tended to be larger, whereas compliance was smaller in women with GDM but none of these differences were significant. Serum glucose (4.99 ± 0.51 vs. 4.79 ± 0.61 mmol/L, p=0.37) and HbA1c (5.33 ± 0.27 vs. 5.36 ± 0.47 mmol/L, p=0.85) proved normoglycemia in both groups. In conclusion, by the combination of methods we applied in this case control study, neither morphological nor functional characteristics of large elastic arteries differ significantly between well-treated normoglycemic women with GDM and non-diabetic pregnant women in the 3rd trimester.

Potentiation of buprenorphine antinociception with ultra-low dose naltrexone in healthy subjects.

Previous reports have demonstrated greater antinociception following administration of a buprenorphine/naloxone combination compared to buprenorphine alone among healthy volunteers. The aim of the current investigation was to determine whether buprenorphine antinociception could be enhanced with the addition of ultra-low dose naltrexone, using a range of dose ratios. A repeated-measures, double-blind, cross-over trial was undertaken with 10 healthy participants. The effects of each buprenorphine:naltrexone ratio (100:1, 133:1, 166:1, and 200:1) on cold pressor tolerance time and respiration were compared to the effects of buprenorphine only. The 166:1 ratio was associated with significantly greater tolerance time to cold pressor pain than buprenorphine alone. Minimal respiratory depression and few adverse events were observed in all conditions. These findings suggest that, as previously described with naloxone, the addition of ultra-low dose naltrexone can enhance the antinociceptive effect of buprenorphine in humans. This potentiation is dose-ratio dependent and occurs without a concomitant increase in adverse effects.

Pharmacokinetics and pharmacodynamics of the short-acting sedative CNS 7056 in sheep.

BACKGROUND: CNS 7056 is a new short-acting esterase-metabolized benzodiazepine. We report the first pharmacokinetic (PK) and pharmacodynamic (PD) study of CNS 7056 and its inactive metabolite CNS 7054 in sheep. METHODS: The stability of CNS 7056 in blood samples was examined ex vivo. Six sheep were prepared with physiological instrumentation, and were given doses of 0.37, 0.74, and 1.47 mg kg(-1) (2 min infusion) of CNS 7056 in alternating order on separate days. RESULTS: CNS 7056 was degraded in warm whole sheep blood (23% over 2 h), but not in plasma or blood stored on ice. Using non-compartmental analysis (NCA), CNS 7056 had a mean (sd) clearance of 4.52 (0.96) litre min(-1) and a terminal half-life of 21.3 (10.9) min. There was a rapid conversion of CNS 7056 to its metabolite CNS 7054, which had a terminal half-life of 22.5 (3.4) min. The arterial kinetics of CNS 7056 could be described by a three-compartment model, with volumes of 1.9, 3.9, and 79 litre, a clearance of 4.2 litre min(-1), and inter-compartmental clearances of 2.85 and 1.44 litre min(-1), while the metabolite could be described by a two-compartment model. Cardiac output was an important covariate. Sedation as measured by the alpha power band of the EEG showed rapid onset and offset. The t(1/2,)(k)(e0) for sedation was 1.78 min, and the EC(50) was 0.10 µg ml(-1). CONCLUSIONS: CNS 7056 has PK-PD properties compatible with its potential human use as a short-acting i.v. sedative.

Safety and efficacy of rituximab in nonviral cryoglobulinemia vasculitis: data from the French Autoimmunity and Rituximab registry.

OBJECTIVE: Management of nonviral cryoglobulinemia vasculitis has yet to be defined. Rituximab has emerged as a novel and promising therapeutic alternative, but data are scarce. Our objective was to evaluate the safety and efficacy of rituximab in nonviral cryoglobulinemia vasculitis in off-trial real-life patients. METHODS: Prospective data from the French AutoImmunity and Rituximab (AIR) registry, which includes data on patients with autoimmune disorders treated with rituximab in off-label conditions, were analyzed. RESULTS: Twenty-three patients received treatment with rituximab for cryoglobulinemia vasculitis. Tolerance was marked by the occurrence of side effects in almost half of the patients, including severe infections in 6 (26%) of 23, with a rate of 14.1 per 100 patient-years. These infections occurred in a particular subset of patients ages>70 years, with essential type II mixed cryoglobulinemia and renal failure with a glomerular filtration rate of <60 ml/minute, and receiving high-dose corticosteroids. Three of these patients died. In contrast, clinical and immunologic efficacy was noted in all evaluable patients. Clinical relapses occurred in half of the patients after a median time of 13.5 months following rituximab administration, and were more frequent in patients refractory to previous immunosuppressive therapy than in previously untreated patients. CONCLUSION: Data from the AIR registry show a dramatic efficacy and a steroid-sparing effect of rituximab, but also show the occurrence of severe infections in elderly patients with renal failure and high-dose steroids. The role of rituximab in nonviral cryoglobulinemia vasculitis remains to be defined in well-designed randomized controlled trials.

Possible involvement of toll-like receptor 4/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences.

Opioid-induced glial activation and its proinflammatory consequences have been associated with both reduced acute opioid analgesia and the enhanced development of tolerance, hyperalgesia and allodynia following chronic opioid administration. Intriguingly, recent evidence demonstrates that these effects can result independently from the activation of classical, stereoselective opioid receptors. Here, a structurally disparate range of opioids cause activation of signaling by the innate immune receptor toll like receptor 4 (TLR4), resulting in proinflammatory glial activation. In the present series of studies, we demonstrate that the (+)-isomers of methadone and morphine, which bind with negligible affinity to classical opioid receptors, induced upregulation of proinflammatory cytokine and chemokine production in rat isolated dorsal spinal cord. Chronic intrathecal (+)-methadone produced hyperalgesia and allodynia, which were associated with significantly increased spinal glial activation (TLR4 mRNA and protein) and the expression of multiple chemokines and cytokines. Statistical analysis suggests that a cluster of cytokines and chemokines may contribute to these nociceptive behavioral changes. Acute intrathecal (+)-methadone and (+)-morphine were also found to induce microglial, interleukin-1 and TLR4/myeloid differentiation factor-2 (MD-2) dependent enhancement of pain responsivity. In silico docking analysis demonstrated (+)-naloxone sensitive docking of (+)-methadone and (+)-morphine to human MD-2. Collectively, these data provide the first evidence of the pro-nociceptive consequences of small molecule xenobiotic activation of spinal TLR4 signaling independent of classical opioid receptor involvement.

Benzodiazepine dependence: focus on withdrawal syndrome.

Benzodiazepines are potentially addictive drugs: psychological and physical dependence can develop within a few weeks or years of regular or repeated use. The socioeconomic costs of the present high level of long-term benzodiazepine use are considerable. These consequences could be minimised if prescriptions for long-term benzodiazepines were decreased. However, many physicians continue to prescribe benzodiazepines and patients wishing to withdraw receive little advice or support. Particular care should be taken in prescribing benzodiazepines for vulnerable patients such as elderly persons, pregnant women, children, alcohol- or drug-dependent patients and patients with comorbid psychiatric disorders. The following update gives recent research results on the withdrawal pathophysiology and practical information in order to treat or prevent benzodiazepine withdrawal syndrome.